Cefprozil, an oral cephalosporin antibiotic, is a mixture of antibiotic BMY-28100 of formula I (the Z- or cis-isomer) and antibiotic BMY-28167 of formula II (the E- or trans-isomer), the mixture having a Z- to E-isomer ratio in the range of 89:11 to 94:6. The preparation of cefprozil is usually carried out using a 3-(Z)-propenyl cephem of formula III.
wherein R is a carboxyl protecting group; R1 is hydrogen or R2CH2CO—; and R2 is ethyl, 2-thiophenyl, phenyl, p-hydroxy or phenoxy.
The propenyl group at position C3 of the cephem compound is usually introduced by the so-called Wittig reaction which produces both Z- and E-isomers of the propenyl double bond. As cefprozil has a Z-isomer content in the range of 89 to 94%, there have been reported many methods for adjusting the Z- to E-isomer ratio, e.g., in the Wittig reaction product.
For example, U.S. Pat. No. 4,699,979 discloses a method of raising the Z- to E-isomer ratio to about 9:1 by conducting a Wittig reaction in the presence of about 10 equivalents of LiBr based on the phosphoranylidene cephem compound with benzylidene amino protection group. However, this method is not applicable to other compounds having an amino protective group other than benzylidene.
U.S. Pat. No. 4,727,070 teaches a method of converting a cefprozil composition containing 85% Z-isomer and 15% E-isomer into an imidazolidinone sodium derivative, removing E-imidazolidinone sodium by a different solubility, and then treating with 1N HCl, to obtain cefprozil containing 98.5% Z-isomer and 1.5% E-isomer. Although the product purity is good, this two-step purification method gives a low yield of about 78%.
International Patent Application No. PCT/EP 92/02965 also discloses a method of lowering the E-isomer content by exploiting solubility differences of various salts of the E- and Z-isomers of deprotected cephem. This method also has disadvantages of a low efficiency and low yield.